CN111234289A - An anti-adhesion polyoxymethylene ligation hemostatic clip and its preparation method and application - Google Patents

Abstract

The invention relates to the field of biomedical engineering, and discloses an anti-adhesion polyformaldehyde ligation hemostatic clamp as well as a preparation method and application thereof, wherein the polyformaldehyde ligation hemostatic clamp is processed by adopting a linear dielectric barrier discharge plasma device, so that an active group and a special thread-shaped micro rough structure are generated on the surface of the polyformaldehyde ligation hemostatic clamp; and then soaking the polyformaldehyde ligation hemostatic clip subjected to surface activation treatment in a mixed solution containing chitosan and carboxymethyl chitosan, so that the chitosan and the carboxymethyl chitosan are uniformly and firmly distributed on the surface of the hemostatic clip to form a composite anti-adhesion film. The anti-adhesion polyformaldehyde ligation hemostatic clip disclosed by the invention achieves the effect of avoiding tissue adhesion after an operation while ensuring the ligation effect, and the degradation time of the composite anti-adhesion film disclosed by the invention can be controlled by adjusting the composite ratio of chitosan and carboxymethyl chitosan so as to adapt to the tissue repair time. The anti-adhesion polyformaldehyde ligation hemostatic clamp disclosed by the invention has a good clinical use effect and is easy to popularize clinically.

Description

An anti-adhesion polyoxymethylene ligation hemostatic clip and its preparation method and application

technical field

The invention relates to the field of biomedical engineering, in particular to an anti-adhesion polyoxymethylene ligation hemostatic clip and a preparation method and application thereof.

Background technique

Avoiding postoperative bile leakage and bleeding is the key link in laparoscopic cholecystectomy. Therefore, it is particularly important to use firm and reliable ligation clips to ligate the cystic duct and cystic artery to avoid and prevent postoperative complications. At present, titanium clips are most used in laparoscopic cholecystectomy. Although titanium clips are cheap and easy to operate, it has been recently found that titanium clips may fall off due to incomplete clipping or be displaced into the bile duct, causing cholangitis, Obstruction or stone formation. At the same time, the titanium clip is conductive, and if the coagulator is in contact, it will cause tissue burns and interfere with imaging examinations.

In recent years, with the development of polymer medical biomaterials, the corresponding products of absorbable hemostatic clips and polymer hemostatic clips have been born, which show great advantages in terms of operability, practical reliability and immunity from magnetic fields; The polyoxymethylene ligation blood vessel clip made of non-absorbable polyoxymethylene material by one injection has been widely used in clinic. However, after using these products in clinical laparoscopic cholecystectomy, severe postoperative adhesions were found. It has been reported that the incidence of adhesion-related ileus after abdominal surgery is as high as 32%, and the probability of reoperation can be as high as 25%. , infertility and chronic pelvic pain. Therefore, it is an urgent clinical need to find a polyoxymethylene ligation hemostatic clip with anti-adhesion effect.

SUMMARY OF THE INVENTION

In view of this, the purpose of the present invention is to provide a kind of anti-adhesion polyoxymethylene ligation hemostatic clip and its preparation method and application. And the degradation time of the composite anti-adhesion film of the anti-adhesion polyoxymethylene ligation hemostatic clip is controllable.

In order to solve the above-mentioned technical problems, the present invention provides a preparation method of an anti-adhesion polyoxymethylene ligation hemostatic clip, comprising the following steps:

1) Put the polyoxymethylene ligation hemostatic clip into an ethanol solution, ultrasonically clean to remove surface impurities, dry, and then perform surface activation treatment with a linear dielectric barrier discharge plasma device;

2) adding chitosan and carboxymethyl chitosan to organic weak acid to prepare a mixed solution, the total concentration of chitosan and carboxymethyl chitosan in the mixed solution is 1-3 wt %, wherein chitosan The mass ratio of carboxymethyl chitosan is 1:9～9:1;

3) Immerse the polyoxymethylene ligation hemostatic clip after the surface activation treatment in step 1) into the mixed solution for 30 minutes, take it out, dry it under vacuum at 40°C, and then immerse it in sodium hydroxide solution for 2 hours, take it out and wash it with deionized water until Neutral, dried in a vacuum at 40° C. to obtain an anti-adhesion polyoxymethylene ligation hemostatic clip.

Preferably, the concentration of the ethanol solution in step 1) is 95wt%.

Preferably, the conditions for the surface activation treatment in step 1) are: the treatment voltage is 120-250v, the treatment power is 250-1000W, the treatment time is 5-1200s, and the treatment atmosphere is vacuum, air, oxygen, argon, nitrogen, One or several mixed atmospheres of ammonia, ethanol vapor and other reactive gases.

Preferably, the conditions of the surface activation treatment in step 1) are: the treatment voltage is 220v, the treatment power is 250-400W, the treatment time is 5-300s, and the treatment atmosphere is vacuum, air or oxygen.

Preferably, the weak organic acid in step 2) is one or both of acetic acid and lactic acid.

Preferably, the concentration of the weak organic acid in step 2) is 2wt%.

Preferably, in the step 2), the mass ratio of chitosan and carboxymethyl chitosan is 4:6-6:4.

Preferably, the concentration of the sodium hydroxide solution in step 3) is 5wt%.

The present invention also provides an anti-adhesion polyoxymethylene ligation hemostatic clip prepared according to the above preparation method.

The invention also provides the application of the above-mentioned anti-adhesion polyformaldehyde ligation hemostatic clip in laparoscopic cholecystectomy.

Compared with the prior art, the present invention uses a linear dielectric barrier discharge plasma device to process the polyoxymethylene ligation hemostatic clip, thereby generating active radicals on its surface, and at the same time forming a special thread-like micro-rough structure on its surface, which greatly improves the performance of the hemostatic clip. The chemical reactivity and roughness of the surface of the polyoxymethylene ligation hemostatic clip material are improved; then the chitosan ligation hemostatic clip is immersed in a mixed solution containing chitosan and carboxymethyl chitosan after the surface activation treatment to make the chitosan The sugar and carboxymethyl chitosan are evenly and firmly distributed on the surface of the hemostatic clip to form a composite anti-adhesion film, and the anti-adhesion polyoxymethylene ligation hemostatic clip of the present invention is obtained. The anti-adhesion polyoxymethylene ligation hemostatic clip prepared by the preparation method of the present invention can ensure the ligation effect while avoiding tissue adhesion after surgery, and the composite anti-adhesion film of the anti-adhesion polyoxymethylene ligation hemostatic clip of the present invention can be adjusted by adjusting chitosan and The compound ratio of carboxymethyl chitosan is used to control the degradation time of the composite anti-adhesion film to adapt to the tissue repair time. For example, in the preparation process, the mass ratio of chitosan and carboxymethyl chitosan is controlled to be 4:6-6:4, and the degradation time is most suitable for the complete repair time of gallbladder tissue. The anti-adhesion polyoxymethylene ligation hemostatic clip of the invention has good clinical application effect and is easy to clinical promotion.

Detailed ways

In order to further understand the present invention, the preferred embodiments of the present invention are described below with reference to the examples, but it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the present invention.

All the raw materials of the present invention, their sources are not particularly limited, can be purchased in the market or prepared according to conventional methods well known to those skilled in the art.

The invention provides a preparation method of an anti-adhesion polyoxymethylene ligation hemostatic clip, comprising the following steps:

1) Put the polyoxymethylene ligation hemostatic clip into an ethanol solution, ultrasonically clean to remove surface impurities, dry, and then perform surface activation treatment with a linear dielectric barrier discharge plasma device;

2) adding chitosan and carboxymethyl chitosan to organic weak acid to prepare a mixed solution, the total concentration of chitosan and carboxymethyl chitosan in the mixed solution is 1-3 wt %, wherein chitosan The mass ratio of carboxymethyl chitosan is 1:9～9:1;

3) Immerse the polyoxymethylene ligation hemostatic clip after the surface activation treatment in step 1) into the mixed solution for 30 minutes, take it out, dry it under vacuum at 40°C, and then immerse it in sodium hydroxide solution for 2 hours, take it out and wash it with deionized water until Neutral, dried in a vacuum at 40° C. to obtain an anti-adhesion polyoxymethylene ligation hemostatic clip.

The present invention firstly performs surface activation treatment on the polyoxymethylene ligation hemostatic clip. Specifically: put the polyoxymethylene ligation hemostatic clip into an ethanol solution, preferably an ethanol solution with a concentration of 95wt%, ultrasonically clean to remove surface impurities, then put it into a vacuum oven for drying, and then use a linear dielectric barrier discharge plasma (narrow type). Plasma) device performs surface activation treatment to generate active radicals on the surface of the POM ligated hemostatic clip, and at the same time, a special thread-like micro-rough structure is formed on the surface, which greatly improves the chemical reactivity and roughness of the surface of the POM ligated hemostatic clip. In the present invention, there are requirements for the conditions of surface activation treatment, wherein the treatment voltage is preferably 120-250v, more preferably 150-250v, the treatment power is preferably 250-1000W, more preferably 250-400w, and the treatment time is preferably 5- 1200s, more preferably 5～300s, the treatment atmosphere is preferably one or more mixed gas atmospheres selected from vacuum, air, oxygen, argon, nitrogen, ammonia, ethanol vapor and other reactive gases, more preferably be vacuum, air or oxygen.

Then, chitosan and carboxymethyl chitosan are compounded according to a certain mass ratio, and organic weak acid is added to configure a mixed solution for anti-adhesion treatment of the polyoxymethylene ligation hemostatic clip. Chitosan is a straight-chain amino polysaccharide formed by the condensation of N-acetylglucosamine through β-1,4-glycosidic bonds, and is the product of deacetylation of chitin. Chitin is a natural macromolecular compound widely found in arthropods such as shrimp and crab shells. Chitosan has the functions of hemostasis and biological barrier, especially can selectively inhibit the growth of fibroblasts, and at the same time promote the growth of epithelial cells and vascular endothelial cells, thus effectively preventing tissue adhesion without affecting the normal healing of tissues. more ideal material. The disadvantage is that the chitosan film is very hard and brittle, and the tissue flexibility is not adaptable enough. Carboxymethyl chitosan is a carboxymethylated derivative of chitosan, soluble in water, and also has excellent biological safety. It can effectively prevent the occurrence of tissue adhesion. It acts as a biological barrier to mechanically isolate inflammatory factors, and the final products of degradation are water and carbon dioxide, which can dilute inflammatory factors. Due to its good solubility, it also has a strong osmotic effect, which changes the selective permeability of cell membranes, thereby playing a bacteriostatic effect. At the same time, it promotes the growth of epithelial cells, restores tissue integrity, and reduces inflammation; it inhibits the growth of fibroblasts, thereby inhibiting the secretion of collagen and reducing adhesion. Carboxymethyl chitosan tissue flexibility adaptability, but the disadvantage is that it dissolves and degrades quickly. In the present invention, chitosan and carboxymethyl chitosan are mixed and dissolved in weak organic acid, so that the anti-adhesion material with good film-forming property and degradable absorption can be prepared. In the present invention, the total concentration of chitosan and carboxymethyl chitosan in the mixed solution is 1-3 wt%, preferably 2 wt%, and the mass ratio of chitosan and carboxymethyl chitosan is 1:9-9: 1, preferably 4:6 to 6:4. In the preparation process of the present invention, the degradation time of the composite anti-adhesion film can be controlled by adjusting the composite ratio of chitosan and carboxymethyl chitosan. In the present invention, the organic weak acid is preferably one or both of acetic acid and lactic acid, more preferably lactic acid. The concentration of the weak organic acid is preferably 2 wt%.

Finally, anti-adhesion treatment is performed on the polyoxymethylene ligation hemostatic clip after the surface activation treatment. Specifically: immerse the polyoxymethylene ligation hemostatic clip after surface activation treatment in the mixed solution for 30 minutes, take it out, dry it under vacuum at 40°C, immerse it in sodium hydroxide solution for 2 hours, take it out and wash it with deionized water until it becomes neutral, and finally After drying at 40°C in vacuum, a composite anti-adhesion film firmly combined with the POM ligated hemostatic clip was formed on the surface of the POM ligated hemostatic clip to obtain an anti-adhesion POM ligated hemostatic clip. Among them, the concentration of the sodium hydroxide solution is preferably 5 wt %. In the process of anti-adhesion treatment, the active group amino group on chitosan and carboxymethyl chitosan is used to connect with the active group generated on the surface of the polyoxymethylene ligation hemostatic clip after surface activation treatment, so that the chitosan Sugar and carboxymethyl chitosan are evenly and firmly distributed on the surface of the polyformaldehyde ligation hemostatic clip to achieve the effect of preventing adhesion.

The present invention also provides an anti-adhesion polyoxymethylene ligation hemostatic clip prepared according to the above-mentioned preparation method.

The invention also provides the application of the above-mentioned anti-adhesion polyformaldehyde ligation hemostatic clip in laparoscopic cholecystectomy.

In order to further illustrate the present invention, an anti-adhesion polyoxymethylene ligation hemostatic clip provided by the present invention and a preparation method thereof are described in detail below with reference to the examples.

Example 1

(1) Surface activation treatment: put the polyoxymethylene ligation hemostatic clip into 95wt% ethanol, ultrasonically clean to remove surface impurities, then put it into a vacuum oven, and after drying, use a long and narrow plasma device for surface activation treatment, and the treatment voltage is 220v, the processing power is 300w, the processing time is 300s, and the processing atmosphere is oxygen.

(2) 18 g of chitosan and 2 g of carboxymethyl chitosan are compounded, and 980 g of lactic acid solution with a concentration of 2 wt % is added to prepare a 1000 g mixed solution.

(3) Anti-adhesion treatment: The polyoxymethylene ligation hemostatic clip after surface activation treatment is immersed in the mixed solution for 30 minutes, taken out from the solution, dried under vacuum at 40°C, and then immersed in a sodium hydroxide solution with a mass concentration of 5% After 2 hours, it was taken out and washed with deionized water for 12 hours, washed to neutrality, and dried under vacuum at 40°C to obtain the anti-adhesion polyoxymethylene ligation hemostatic clip of this example.

Example 2

(1) Surface activation treatment: put the polyoxymethylene ligation hemostatic clip into 95wt% ethanol, ultrasonically clean to remove surface impurities, then put it into a vacuum oven, and after drying, use a long and narrow plasma device for surface activation treatment, and the treatment voltage is 150v, the processing power is 250w, the processing time is 50s, and the processing atmosphere is vacuum.

(2) 18 g of chitosan and 12 g of carboxymethyl chitosan were compounded, and 970 g of lactic acid solution with a concentration of 2 wt % was added to prepare a 1000 g mixed solution.

(3) Anti-adhesion treatment: The polyoxymethylene ligation hemostatic clip after surface activation treatment is immersed in the mixed solution for 30 minutes, taken out from the solution, dried under vacuum at 40°C, and then immersed in a sodium hydroxide solution with a mass concentration of 5% After 2 hours, it was taken out and washed with deionized water for 12 hours, washed to neutrality, and dried under vacuum at 40°C to obtain the anti-adhesion polyoxymethylene ligation hemostatic clip of this example.

Example 3

(1) Surface activation treatment: put the polyoxymethylene ligation hemostatic clip into 95wt% ethanol, ultrasonically clean to remove surface impurities, then put it into a vacuum oven, and after drying, use a long and narrow plasma device for surface activation treatment, and the treatment voltage is 250v, the processing power is 400w, the processing time is 5s, and the processing atmosphere is air.

(2) 1 g of chitosan and 9 g of carboxymethyl chitosan are compounded, and 990 g of lactic acid solution with a concentration of 2 wt % is added to prepare a 1000 g mixed solution.

(3) Anti-adhesion treatment: The polyoxymethylene ligation hemostatic clip after surface activation treatment is immersed in the mixed solution for 30 minutes, taken out from the solution, dried under vacuum at 40°C, and then immersed in a sodium hydroxide solution with a mass concentration of 5% After 2 hours, it was taken out and washed with deionized water for 12 hours, washed to neutrality, and dried under vacuum at 40°C to obtain the anti-adhesion polyoxymethylene ligation hemostatic clip of this example.

Comparative ratio

The common polyformaldehyde ligation hemostatic clip used in clinic was used as a control.

test case

Appearance property test: the anti-adhesion polyoxymethylene ligation hemostatic clip obtained in Examples 1 to 3 has a uniform anti-adhesion film coating on the surface and no irritation.

Anti-adhesion effect test: drop fibroblasts (PFF) on the anti-adhesion polyoxymethylene ligation hemostatic clips obtained in Examples 1 to 3 and the ordinary polyoxymethylene ligation hemostatic clips of the comparative example, and then put these hemostatic clips into carbon dioxide cells. After culturing in the incubator for 24 hours, staining was performed, and then the growth and adhesion state of cells on the material were observed by fluorescence microscope. The smaller the number of cells adhered to the material, the less likely the cells were to adhere to the surface of the material, and the better the adhesion resistance.

Degradation test: The anti-adhesion polyoxymethylene ligation hemostatic clip obtained in Examples 1-3 was immersed in a 2% lysozyme solution, and the solution was changed every two days for observation. The time when the composite anti-adhesion film breaks is the degradation time.

The test results are shown in Table 1.

Table 1

sample Example 1 Example 2 Example 3 Comparative ratio irritating none none none — sticking effect no adhesion no adhesion no adhesion have adhesions degradation time 157 days 93 days 65 days —

As can be seen from Table 1, the anti-adhesion polyoxymethylene ligation hemostatic clip of the present invention is non-irritating, and the anti-adhesion effect is good, and the degradation time of the composite anti-adhesion film can be controlled by adjusting the composite ratio of chitosan and carboxymethyl chitosan, and The smaller the proportion of chitosan, the shorter the degradation time. Among them, in Example 2, the degradation time of the composite anti-adhesion film was 93 days, which was basically the same as the complete repair time of the gallbladder tissue.

While the basic principles and main features and advantages of the present invention have been shown and described above, it will be apparent to those skilled in the art that the present invention is not limited to the details of the above-described exemplary embodiments, but without departing from the spirit or essential aspects of the present invention. In the case of the characteristic features, the present invention can be implemented in other specific forms. Therefore, the embodiments are to be regarded in all respects as illustrative and not restrictive, and the scope of the invention is to be defined by the appended claims rather than the foregoing description, which are therefore intended to fall within the scope of the claims. All changes within the meaning and scope of the equivalents of , are included in the present invention. Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, and substitutions can be made in these embodiments without departing from the principle and spirit of the invention and modifications, the scope of the present invention is defined by the appended claims and their equivalents.

Claims (10)

1. The preparation method of the anti-adhesion polyformaldehyde ligation hemostatic clip is characterized by comprising the following steps of:

1) putting the polyformaldehyde ligation hemostatic clamp into an ethanol solution, ultrasonically cleaning to remove surface impurities, drying, and then performing surface activation treatment by using a linear dielectric barrier discharge plasma device;

2) adding organic weak acid into chitosan and carboxymethyl chitosan to prepare a mixed solution, wherein the total concentration of the chitosan and the carboxymethyl chitosan in the mixed solution is 1-3 wt%, and the mass ratio of the chitosan to the carboxymethyl chitosan is 1: 9-9: 1;

3) immersing the polyformaldehyde ligation hemostatic clip subjected to the surface activation treatment in the step 1) into the mixed solution for 30min, taking out, drying at 40 ℃ in vacuum, immersing in a sodium hydroxide solution for 2h, taking out, washing with deionized water to be neutral, and drying at 40 ℃ in vacuum to obtain the anti-adhesion polyformaldehyde ligation hemostatic clip.

2. The method according to claim 1, wherein the concentration of the ethanol solution in the step 1) is 95 wt%.

3. The production method according to claim 1, wherein the conditions of the surface activation treatment in step 1) are: the processing voltage is 120-250 v, the processing power is 250-1000W, the processing time is 5-1200 s, and the processing atmosphere is one or a mixture of several of vacuum, air, oxygen, argon, nitrogen, ammonia, ethanol steam and other gases with reactivity.

4. The production method according to claim 1, wherein the conditions of the surface activation treatment of step 1) are: the processing voltage is 220v, the processing power is 250-400W, the processing time is 5-300 s, and the processing atmosphere is vacuum, air or oxygen.

5. The method according to claim 1, wherein the weak organic acid in step 2) is one or both of acetic acid and lactic acid.

6. The method according to claim 1, wherein the weak organic acid in step 2) has a concentration of 2 wt%.

7. The preparation method according to claim 1, wherein the mass ratio of the chitosan to the carboxymethyl chitosan in the step 2) is 4:6 to 6: 4.

8. The method according to claim 1, wherein the concentration of the sodium hydroxide solution in the step 3) is 5 wt%.

9. The anti-adhesion polyformaldehyde ligation hemostatic clip prepared by the preparation method according to any one of claims 1-8.

10. The anti-adhesion polyoxymethylene ligation hemostatic clip of claim 9, for use in laparoscopic cholecystectomy surgery.